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Ventilation and cerebral blood flow (CBF) are both sensitive to hypoxia and hypercapnia. To compare chemosensitivity in these two systems, we made simultaneous measurements of ventilatory and cerebrovascular responses to hypoxia and hypercapnia in 35 normal human subjects before and after acclimatization to hypoxia. Ventilation and CBF were measured during stepwise changes in isocapnic hypoxia and iso-oxic hypercapnia. We used MRI to quantify actual cerebral perfusion. Measurements were repeated after 2 days of acclimatization to hypoxia at 3,800 m altitude (partial pressure of inspired O 2 = 90 Torr) to compare plasticity in the chemosensitivity of these two systems. Potential effects of hypoxic and hypercapnic responses on acute mountain sickness (AMS) were assessed also. The pattern of CBF and ventilatory responses to hypercapnia were almost identical. CO 2 responses were augmented to a similar degree in both systems by concomitant acute hypoxia or acclimatization to sustained hypoxia. Conversely, the pattern of CBF and ventilatory responses to hypoxia were markedly different. Ventilation showed the well-known increase with acute hypoxia and a progressive decline in absolute value over 25 min of sustained hypoxia. With acclimatization to hypoxia for 2 days, the absolute values of ventilation and O 2 sensitivity increased. By contrast, O 2 sensitivity of CBF or its absolute value did not change during sustained hypoxia for up to 2 days. The results suggest a common or integrated control mechanism for CBF and ventilation by CO 2 but different mechanisms of O 2 sensitivity and plasticity between the systems. Ventilatory and cerebrovascular responses were the same for all subjects irrespective of AMS symptoms. NEW & NOTEWORTHY Ventilatory and cerebrovascular hypercapnic response patterns show similar plasticity in CO 2 sensitivity following hypoxic acclimatization, suggesting an integrated control mechanism. Conversely, ventilatory and cerebrovascular hypoxic responses differ. Ventilation initially increases but adapts with prolonged hypoxia (hypoxic ventilatory decline), and ventilatory sensitivity increases following acclimatization. In contrast, cerebral blood flow hypoxic sensitivity remains constant over a range of hypoxic stimuli, with no cerebrovascular acclimatization to sustained hypoxia, suggesting different mechanisms for O 2 sensitivity in the two systems.

Low doses of the carbonic anhydrase inhibitor acetazolamide provides accelerated acclimatization to high-altitude hypoxia and prevention of cerebral and other symptoms of acute mountain sickness. We previously observed increases in cerebral O2 metabolism (CMRO2 ) during hypoxia. In this study, we investigate whether low-dose oral acetazolamide (250 mg) reduces this elevated CMRO2 and in turn might improve cerebral tissue oxygenation (PtiO2 ) during acute hypoxia. Six normal human subjects were exposed to 6 h of normobaric hypoxia with and without acetazolamide prophylaxis. We determined CMRO2 and cerebral PtiO2 from MRI measurements of cerebral blood flow (CBF) and cerebral venous O2 saturation. During normoxia, low-dose acetazolamide resulted in no significant change in CBF, CMRO2 , or PtiO2 . During hypoxia, we observed increases in CBF [48.5 (SD 12.4) (normoxia) to 65.5 (20.4) ml·100 ml(-1)·min(-1) (hypoxia), P < 0.05] and CMRO2 [1.54 (0.19) to 1.79 (0.25) μmol·ml(-1)·min(-1), P < 0.05] and a dramatic decline in PtiO2 [25.0 to 11.4 (2.7) mmHg, P < 0.05]. Acetazolamide prophylaxis mitigated these rises in CBF [53.7 (20.7) ml·100 ml(-1)·min(-1) (hypoxia + acetazolamide)] and CMRO2 [1.41 (0.09) μmol·ml(-1)·min(-1) (hypoxia + acetazolamide)] associated with acute hypoxia but also reduced O2 delivery [6.92 (1.45) (hypoxia) to 5.60 (1.14) mmol/min (hypoxia + acetazolamide), P < 0.05]. The net effect was improved cerebral tissue PtiO2 during acute hypoxia [11.4 (2.7) (hypoxia) to 16.5 (3.0) mmHg (hypoxia + acetazolamide), P < 0.05]. In addition to its renal effect, low-dose acetazolamide is effective at the capillary endothelium, and we hypothesize that local interruption in cerebral CO2 excretion accounts for the improvements in CMRO2 and ultimately in cerebral tissue oxygenation during hypoxia. This study suggests a potentially pivotal role of cerebral CO2 and pH in modulating CMRO2 and PtiO2 during acute hypoxia., (Copyright © 2015 the American Physiological Society.)

Diffusion magnetic resonance imaging (MRI) provides a sensitive indicator of cerebral hypoxia. We investigated if apparent diffusion coefficient (ADC) and transverse relaxation (T(2)) predict symptoms of acute mountain sickness (AMS), or merely indicate the AMS phenotype irrespective of symptoms. Fourteen normal subjects were studied in two groups; unambiguous AMS and no-AMS at 3,800 m altitude (intermediate AMS scores were excluded). T(2) relaxation was estimated from a T(2) index of T(2)-weighted signal normalized by cerebrospinal fluid signal. Measurements were made in normoxia and repeated after 2 days sustained hypoxia (AMS group symptomatic and no-AMS group asymptomatic) and after 7 days hypoxia (both groups asymptomatic). Decreased ADC directly predicted AMS symptoms (P<0.05). Apparent diffusion coefficient increased in asymptomatic subjects, or as symptoms abated with acclimatization. This pattern was similar in basal ganglia, white matter, and gray matter. Corpus callosum behaved differently; restricted diffusion was absent (or rapidly reversed) in the splenium, and was sustained in the genu. In symptomatic subjects, T(2,index) decreased after 2 days hypoxia and further decreased after 7 days. In asymptomatic subjects, T(2,index) initially increased after 2 days, but decreased after 7 days. T(2,index) changes were not predictive of AMS symptoms. These findings indicate that restricted diffusion, an indicator of diminished cerebral energy status, directly predicts symptoms of AMS in humans at altitude.

Acute mountain sickness (AMS) is a common condition occurring within hours of rapid exposure to high altitude. Despite its frequent occurrence, the pathophysiological mechanisms that underlie the condition remain poorly understood. We investigated the role of cerebral oxygen metabolism (CMR(O(2))) in AMS. The purpose of this study was to test 1) if CMR(O(2)) changes in response to hypoxia, and 2) if there is a difference in how individuals adapt to oxygen metabolic changes that may determine who develops AMS and who does not. Twenty-six normal human subjects were recruited into two groups based on Lake Louise AMS score (LLS): those with no AMS (LLS ≤ 2), and those with unambiguous AMS (LLS ≥ 5). [Subjects with intermediate scores (LLS 3-4) were not included.] CMR(O(2)) was calculated from cerebral blood flow and arterial-venous difference in O(2) content. Cerebral blood flow was measured using arterial spin labeling MRI; venous O(2) saturation was calculated from the MRI of transverse relaxation in the superior sagittal sinus. Arterial O(2) saturation was measured via pulse oximeter. Measurements were made during normoxia and after 2-day high-altitude exposure at 3,800 m. In all subjects, CMR(O(2)) increased with sustained high-altitude hypoxia [1.54 (0.37) to 1.82 (0.49) μmol·g(-1)·min(-1), n = 26, P = 0.045]. There was no significant difference in CMR(O(2)) between AMS and no-AMS groups. End-tidal Pco(2) was significantly reduced during hypoxia. Low arterial Pco(2) is known to increase neural excitability, and we hypothesize that the low arterial Pco(2) resulting from ventilatory acclimatization causes the observed increase in CMR(O(2)).

Acute mountain sickness (AMS) and high-altitude cerebral edema share common clinical characteristics, suggesting cerebral swelling may be an important factor in the pathophysiology of AMS. Hypoxia and hypocapnia associated with high altitude are known to exert strong effects on the control of the cerebral circulation, yet how these effects interact during acute hypoxia, and whether AMS-susceptible subjects may have a unique response, is still unclear. To test if self-identified AMS-susceptible individuals show altered brain swelling in response to acute hypoxia, we used quantitative arterial spin-labeling and volumetric MRI to measure cerebral blood flow and cerebrospinal fluid (CSF) volume changes during 40 min of acute hypoxia. We estimated changes in cerebral blood volume (CBV) (from changes in cerebral blood flow) and brain parenchyma swelling (from changes in CBV and CSF). Subjects with extensive high-altitude experience in two groups participated: self-identified AMS-susceptible (n = 6), who invariably experienced AMS at altitude, and self-identified AMS-resistant (n = 6), who almost never experienced symptoms. During 40-min hypoxia, intracranial CSF volume decreased significantly [-10.5 ml (SD 6.9), P < 0.001]. There were significant increases in CBV [+2.3 ml (SD 2.5), P < 0.005] and brain parenchyma volume [+8.2 ml (SD 6.4), P < 0.001]. However, there was no significant difference between self-identified AMS-susceptible and AMS-resistant groups for these acute-phase changes. In acute hypoxia, brain swelling occurs earlier than previously described, with significant shifts in intracranial CSF occurring as early as 40 min after exposure. These acute-phase changes are present in all individuals, irrespective of susceptibility to AMS.

Unlabelled: Individuals susceptible to high altitude pulmonary edema show altered pulmonary vascular responses within minutes of exposure to hypoxia. We hypothesized that a similar acute-phase vulnerability to hypoxia may exist in the brain of individuals susceptible to acute mountain sickness (AMS). In established AMS and high altitude cerebral edema, there is a propensity for vasogenic white matter edema. We therefore hypothesized that increased cerebral blood flow (CBF) during acute hypoxia would also be disproportionately greater in white matter (WM) than grey matter (GM) in AMS-susceptible subjects. We quantified regional CBF using arterial spin labeling MRI during 30 min hypoxia (F(I)O(2) = 0.125) in two groups: AMS-susceptible (AMS-S, n = 6) who invariably experienced AMS at altitude, and AMS-resistant (AMS-R, n = 6) who never experienced AMS despite multiple rapid ascents to high altitude. SaO(2) during hypoxia did not differ between groups (AMS-S = 87+/-4%, AMS-R = 89+/-3%, p = 0.3). Steady-state whole-brain CBF increased in hypoxia (p<0.005), but did not differ between groups (normoxia: AMS-S = 42.7+/-14.0 ml/(100 g min), AMS-R = 41.7+/-10.1 ml/(100 g min); hypoxia: AMS-S = 47.8+/-19.5 ml/(100 g min), AMS-R = 48.2+/-10.1 ml/(100 g min), p = 0.65), and cerebral oxygen delivery remained constant. The percent change in CBF did not differ between brain regions or between groups (although absolute CBF change was greater in GM): (GM: AMS-S = 6.1+/-7.7 ml/(100 g min) (10+/-11%), AMS-R = 8.3+/-5.7 ml/(100 g min) (17+/-11%), p = 0.57; WM: AMS-S = 4.3+/-5.1 ml/(100 g min) (12+/-15%), AMS-R = 4.8+/-2.9 ml/(100 g min) (16+/-9%), p = 0.82)., Conclusion: CBF increases in acute hypoxia, but is not different between WM and GM, irrespective of AMS susceptibility. Acute phase differences in regional CBF during acute hypoxia are not a primary feature of susceptibility to AMS.

Low doses of the carbonic anhydrase inhibitor acetazolamide provides accelerated acclimatization to high-altitude hypoxia and prevention of cerebral and other symptoms of acute mountain sickness. We previously observed increases in cerebral O2 metabolism (CMRO2) during hypoxia. In this study, we investigate whether low-dose oral acetazolamide (250 mg) reduces this elevated CMRO2 and in turn might improve cerebral tissue oxygenation (PtiO2) during acute hypoxia. Six normal human subjects were exposed to 6 h of normobaric hypoxia with and without acetazolamide prophylaxis. We determined CMRO2 and cerebral PtiO2 from MRI measurements of cerebral blood flow (CBF) and cerebral venous O2 saturation. During normoxia, low-dose acetazolamide resulted in no significant change in CBF, CMRO2, or PtiO2. During hypoxia, we observed increases in CBF [48.5 (SD 12.4) (normoxia) to 65.5 (20.4) ml·100 ml−1·min−1 (hypoxia), P < 0.05] and CMRO2 [1.54 (0.19) to 1.79 (0.25) μmol·ml−1·min−1, P < 0.05] and a dramatic decline in PtiO2 [25.0 to 11.4 (2.7) mmHg, P < 0.05]. Acetazolamide prophylaxis mitigated these rises in CBF [53.7 (20.7) ml·100 ml−1·min−1 (hypoxia + acetazolamide)] and CMRO2 [1.41 (0.09) μmol·ml−1·min−1 (hypoxia + acetazolamide)] associated with acute hypoxia but also reduced O2 delivery [6.92 (1.45) (hypoxia) to 5.60 (1.14) mmol/min (hypoxia + acetazolamide), P < 0.05]. The net effect was improved cerebral tissue PtiO2 during acute hypoxia [11.4 (2.7) (hypoxia) to 16.5 (3.0) mmHg (hypoxia + acetazolamide), P < 0.05]. In addition to its renal effect, low-dose acetazolamide is effective at the capillary endothelium, and we hypothesize that local interruption in cerebral CO2 excretion accounts for the improvements in CMRO2 and ultimately in cerebral tissue oxygenation during hypoxia. This study suggests a potentially pivotal role of cerebral CO2 and pH in modulating CMRO2 and PtiO2 during acute hypoxia. [ABSTRACT FROM AUTHOR]